Brain iron in ageing: Pixels to pathways

Abstract

Nigrostriatal iron deposition is a reproducible feature of brain ageing and Parkinsonian neurodegeneration, but its biological and therapeutic significance remains incompletely understood. Iron-sensitive MRI methods, including quantitative susceptibility mapping (QSM) and related approaches, can localize regional susceptibility changes in the substantia nigra and striatum in vivo, yet imaging alone cannot distinguish whether these changes reflect adaptive iron storage, impaired trafficking, mitochondrial stress, inflammatory activation, neuromelanin-associated iron, ferroptosis-like vulnerability, or downstream neurodegeneration. Despite recent emphasis on metabolic dysfunction, inflammaging, proteostasis failure, mitophagy and other ageing pathways, iron biology intersects with these processes in ways that are still poorly resolved at the molecular level. This editorial argues that nigrostriatal iron-sensitive MRI should be reframed as a molecularly informative endophenotype. Integrating it with population-scale genomic, transcriptomic and multi-omic data offers a route to identify the genes, pathways and cell types regulating iron accumulation, distinguish physiological ageing from pathological dysregulation, prioritize therapeutic targets and support biomarker-guided intervention strategies in aging-related neurodegenerative disease.

Keywords: Nigrostriatal iron, ageing, Parkinson’s disease, post-GWAS, omics, therapeutic target discovery